Fumaric acid amides

ABSTRACT

Fumaric acid amides of the general formula (I) 
                         
wherein R 1  represents OR 3  or a D- or L-amino acid radical —NH—CHR 4 —COOH bonded via an amide bond, wherein R 3  is hydrogen, a straight-chained or branched, optionally substituted C 1-24  alkyl radical, a phenyl radical or C 6-10  aralkyl radical and R 4  is a side chain of a natural or synthetic amino acid and R 2  represents a D- or L-amino acid radical —NH—CHR 5 —COOH bonded via an amide bond or a peptide radical comprising 2 to 100 amino acids bonded via an amide bond, wherein R 5  is a side chain of a natural or synthetic amino acid, are used for preparing a drug (1) for the therapy of an autoimmune disease; (2) for use in transplantation medicine; (3) for the therapy of mitochondrial diseases; or (4) for the therapy of NF-kappaB mediated diseases.

REFERENCE TO RELATED APPLICATIONS

This application is a 371 continuation of PCT Application PCT/EP02/00107, filed Jan. 8, 2002, the text of which is not in English, which PCT Application claims priority on German Application No. 101 01 307.8, filed Jan. 12, 2001, and German Application No. 101 33 004.9, filed Jul. 6, 2001, neither text of which is in English.

TECHNICAL FIELD

The present invention relates to certain fumaric acid mono- and diamides, or monoamido fumaric acid monoesters, respectively, as well as the use of such compounds for preparing a drug and drugs containing said compounds.

BACKGROUND

For a long time, fumaric acid dialkyl esters as well as fumaric acid monoalkyl esters and salts thereof have been successfully used for treating psoriasis. Said use is described in a number of patents, for example EP-A-0 188 749, DE-95 30 327, DE 26 21 214 or EP-B-0 312 697.

The use of fumaric acid mono- or diesters is also described for the treatment of autoimmune diseases such as polyarthritis, multiple sclerosis (cf. DE 197 21 099.6 and DE 198 53 487.6), but also for use in transplantation medicine (cf. DE 198 53 487.6 and DE 198 39 566.3). The use of fumaric acid mono- and diesters for the treatment of NF-kappaB mediated diseases and the treatment of mitochondrial diseases is also known from the unpublished German applications DE 101 01 307.8 and DE 100 00 577.2. However, all the cited documents merely describe fumaric acid mono- and diesters, optionally in the form of certain salts, i.e. compounds wherein one or both acid functions of the fumaric acid are esterified with an alcohol.

Because of their volatility and sublimability, however, the above-mentioned fumaric acid esters have the disadvantage of being difficult to handle when preparing pharmaceutical products, especially those in solid form for oral administration. Specifically the preparation of such products requires protective measures such as the use of breathing masks, gloves, protective clothing.

In addition, the fumaric acid esters are absorbed in the gastro-intestinal tract after oral administration and taken up unspecifically from the bloodstream by all body cells. Therefore, it is necessary to administer high dosages in order to provide a therapeutically effective level of the active ingredient on or in the target cells.

Such high dosages in turn lead to the known side effects of a fumaric acid therapy like flush symptoms (reddening) or gastrointestinal irritation (nausea, diarrhoea, winds). Even though such side effects may be reduced considerably by administering the active ingredient in the form of micro-tablets as described in the above-cited prior art, they cannot be avoided altogether.

At the same time, the fumaric acid esters are rapidly hydrolysed in the blood and the products of said hydrolysis, alcohol and fumaric acid or fumaric acid monoester, metabolised. In order to maintain therapeutically effective levels repeated and frequent administration is therefore necessary. Even though a certain adaptation is observed concerning the side effects, a further reduction of the side effect rate would be desirable.

BRIEF SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide fumaric acid derivatives, which may be administered strategically, are more resistant to hydrolysis and easier to handle, and the use of such derivatives.

The present object is achieved by certain fumaric acid mono- and diamides or monoamido fumaric acid monoesters, respectively, the use thereof for preparing drugs for the therapy of certain diseases and drugs containing the same.

FURTHER DETAILED DESCRIPTION OF THE INVENTION

Fumaric acid diamides and monoamides have also been described in U.S. Pat. No. 5,242,905 and U.S. Pat. No. 5,214,196 to Blank for the treatment of psoriasis. However, these cited publications merely describe the preparation of single fumaric acid mono- or diamides, but not the preparation of pharmaceutical products and the application of the amides on human beings. A theoretical advantage of the fumaric amides over the fumaric acid esters cited by the above publications is the provision of certain amino acids from the fumaric amides in the keratinocytes in order to complement metabolic deficiencies in psoriasis.

Surprisingly, the inventors have now found that the fumaric acid mono- and diamides or monoamido fumaric acid monoesters may be used advantageously for the therapy of a variety of diseases. Specifically, the first aspect of the present invention therefore relates to the use of fumaric acid amides of the general formula (I)

wherein

R¹ represents OR³ or a D- or L-amino acid radical —NH—CHR⁴—COOH bonded via an amide bond, wherein R³ is hydrogen, a straight-chained or branched, optionally substituted C₁₋₂₄ alkyl radical, preferably a C₁₋₆ alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R⁴ is a side chain of a natural or synthetic amino acid and R² represents a D- or L-amino acid radical —NH—CHR⁵—COOH bonded via an amide bond or a peptide radical comprising 2 to 100, preferably 2 to 30 amino acids bonded via an amide bond, wherein R⁵ is a side chain of a natural or synthetic amino acid,

for preparing a drug

-   -   (1) for the therapy of an autoimmune disease selected from the         group consisting of polyarthritis, especially rheumatoid         arthritis, multiple sclerosis, graft-versus-host reactions,         juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's         disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome,         pernicious anaemia and chronic active (=lupoid) hepatitis;     -   (2) for use in transplantation medicine         (Host-versus-graft-reactions);     -   (3) for the therapy of mitochondrial diseases selected from the         group consisting of Parkinson syndrome, Alzheimer's disease,         Chorea Huntington disease, retinopathia pigmentosa or forms of         mitochondrial encephalomyopathy; as well as     -   (4) for the therapy of NF-kappaB mediated diseases selected from         the group consisting of progressive systemic sclerodermia,         osteochondritis syphilitica (Wegener's disease), cutis marmorata         (livedo reticularis), Behcet disease, panarteriitis, colitis         ulcerosa, vasculitis, osteoarthritis, gout, artenosclerosis,         Reiter's disease, pulmonary granulomatosis, types of         encephalitis, endotoxic shock (septic-toxic shock), sepsis,         pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (acute         hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced         hepatitis, viral hepatitis, jaundice, liver insufficiency and         cytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangial         nephritis, post-angioplastic restenosis, reperfusion syndrome,         cytomegaloviral retinopathy, adenoviral diseases such as         adenoviral colds, adenoviral pharyngoconjunctival fever and         adenoviral ophthalmia, AIDS, Guillain-Barré syndrome,         post-herpetic or post-zoster neuralgia, inflammatory         demyelinising polyneuropathy, mononeuropathia multiplex,         mucoviscidosis, Bechterew's disease, Barett oesophagus, EBV         (Epstein-Barr virus) infection, cardiac remodeling, interstitial         cystitis, diabetes mellitus type II, human tumour         radiosensitisation, multi-resistance of malignant cells to         chemotherapeutic agents (multidrug resistance in chemotherapy),         granuloma annulare and cancers such as mamma carcinoma, colon         carcinoma, melanoma, primary liver cell carcinoma,         adenocarcinoma, kaposi's sarcoma, prostate carcinoma, leukaemia         such as acute myeloid leukaemia, multiple myeloma         (plasmocytoma), Burkitt lymphoma and Castleman tumour.

In a second aspect, the present invention relates to fumaric acid amides of the formula (I)

wherein

R¹ represents OR³ or a D- or L-amino acid radical —NH—CHR⁴—COOH bonded via an amide bond, wherein R³ is hydrogen, a straight-chained or branched, optionally substituted C₁₋₂₄ alkyl radical, preferably a C₁₋₆ alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R₄ is a side chain of a natural or synthetic amino acid and

R² represents a D- or L-amino acid radical —NH—CHR⁵—COOH bonded via an amide bond or a peptide radical comprising 2 to 100 amino acids, preferably 2 to 30 amino acids, bonded via an amide bond, wherein R⁵ is a side chain of a natural or synthetic amino acid,

with the proviso that

-   -   when R³═H, R² is a peptide radical selected from the group         consisting of peptide hormones, growth factors, cytokines,         neurotransmitters, neuropeptides, antibody fragments,         coagulation factors and cyclosporines as well as derivatives and         fragments thereof; and     -   when R¹═NH—CHR⁴—COOH, R² is a peptide radical selected from the         group consisting of peptide hormones, growth factors, cytokines,         neurotransmitters, neuropeptides, antibody fragments,         cyclosporines and coagulation factors as well as derivatives and         fragments thereof, or represents —NH—CHR⁵—COOH wherein R⁵ is         selected from the group consisting of the side chains of Ala,         Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys,         Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

The term “side chain of a natural or synthetic amino acid” means the radicals of each natural or synthetic amino acid positioned on the α-carbon atom. The amino acid radicals R¹ and R² may be present in the D- and the L-configuration, the natural L-configuration being preferred. Below, the customary abbreviations and designations in the 3-letter code are used to characterise the amino acids.

According to one embodiment, especially compounds of the formula (I) are used and claimed, respectively, wherein R¹ represents —NH—CHR⁴—COOH and R² represents —NH—CHR⁵—COOH wherein R⁴ and R⁵ may be the same or different and are as defined above. More preferably, R⁴ and R⁵ are independently selected from the group consisting of the side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

According to another embodiment, compounds of the formula (I) are used or claimed, respectively, wherein R¹ represents —OR³ and R² represents an L-amino acid radical —NH—CHR⁵—COOH, wherein R⁵ is selected from the group consisting of the side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

Especially preferably R⁵ is a polar amino acid in both embodiments, even more preferably a charge-bearing amino acid selected from the group consisting of asparagine, glutamine, lysine, arginine and histidine.

When the radical R¹ represents —OR³, i.e. when the compound of the formula (I) to be used according to the invention or claimed, respectively, is a monoamido fumaric acid monoester or monoamide, R₃ is preferably selected from the group consisting of a linear, branched, cyclic, saturated or unsaturated C₁₋₂₄ alkyl radical, preferably a C₁₋₆ alkyl radical, a phenyl radical or a C₆₋₁₀ aralkyl radical and this radical is optionally substituted with halogen (F, Cl, Br, I), hydroxy, C₁₋₄ alkoxy, nitro or cyano. Preferably R³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl, methoxymethyl or 2- or 3-methoxypropyl. Most preferably R³ is methyl or ethyl.

According to another embodiment of the invention, compounds of the formula (I) are used wherein R¹ represents —OR³, preferably with R³=methyl or ethyl, and R² represents a peptide radical with 2 to 100, preferably 2 to 30 amino and most preferably 5 to 25 amino acids bonded via an amide bond. Said peptide radical may be a natural, recombinant or synthetic peptide radical.

More preferably, the peptide radical R² is selected from the group consisting of peptide hormones, growth factors, cytokines, neurotransmitters, neuropeptides, antibody fragments, coagulation factors and cyclosporines as well as derivatives and fragments thereof. Said peptides may be purified from natural sources, recovered by recombinant methods or synthesised in accordance with known processes. The use of synthetic peptides is preferred.

Coupling the fumaric acid body to such a functional peptide has the advantage of the peptide providing a transmission of the active ingredient “fumaric acid body” to target cells with which the peptide portion of the amides of the invention interacts. At the same time, the peptide portion may have its own effect on the disease to be treated so that a combination therapy is effected in this case. However, a combination therapy and/or strategic administration permit reduction of the dose to be administered in a desirable, possibly even synergistic manner.

According a preferred embodiment of the invention, the peptide radical may be a cyclosporine radical the cycle of which may be cleaved at each peptide bond in order to enter into the fumaric acid amide bonding. In general, all cyclosporines may be bonded to the fumaric acid body by an amide bond in the invention. Since cyclosporines are cyclic peptides, the peptide ring is generally cleaved at any position (at any amide bond) in order to obtain a linearised cyclosporine capable of entering into an amide bond. Preferably cyclosporine A linearised before position 1 is used.

The term “peptide hormones” as used here means physiologically highly active peptides with approximately up to 100 amino acids which develop a hormone effect or hormone-like effect. Examples are the glandular peptide hormones of the pituitary gland such as corticotropin, follitropin, lutropin, melanotropin, prolactin, somatotropin, thyrotropin, oxytocin and vasopressin, the releasing hormones and inhibiting factors of the hypothalamus, the peptide hormones from the pancreas, stomach or intestine such as glucagon, insulin, somatostatin, sectretin, gastrin and cholecystokinin, the peptide hormones of the thyroid such as calcitonin, parathyrin and such like.

The term “growth factors” means hormone-like peptides and proteins which support cell division and cell differentiation, promote growth and organ development and are needed for wound healing. Examples are colony-stimulating factors, the epidermal growth factor (EGF), erythropoietin, fibroblast growth factors, haematopoietic growth factors, hepatocyte growth factors, insulin and insulin-like growth factors, the platelet-derived growth factor (PDGF), thrombopoietin, transforming growth factors, viral growth factors, but the interleukins, too.

The term “cytokines” as used in the present application refers to polypeptides which are secreted by cells and, after bonding with specific receptors, may influence the function of other, usually adjacent cells. Cytokines primarily regulate the complex interaction of the cells of the immune system. Examples of such cytokines are interferons, interleukins, chemokines or colony-stimulating factors.

The term “neurotransmitter” means messenger substances which effect the chemical signal or information transmission on the synapses of the nervous system. Depending on their chemical characteristics, neurotransmitters are divided into amino acids such as glutamine acid, amino acid derivatives such as acetylcholine, monoamines like the catechol amines, such as L-noradrenalin, L-adrenalin and dopamine, serotonin and peptides. Accordingly, the “neuropeptides” like bradykinin, but also the enkephalines, endorphin etc. are a sub-group of the neurotransmitters.

The term “coagulation factors” as used here means proteins of the coagulation cascade. Likewise, the peptide which, in the invention, may be coupled to the fumaric acid via an amide-bonding may be an antibody fragment, said fragment preferably also comprising a recognition sequence and/or bonding sequence.

Fragments and/or derivatives of all the peptides enumerated above which are suitable for the invention may also be used. The term “fragment” means a portion of the above-mentioned peptides which is capable of amide bonding. Preferably, said fragment comprises recognition sequences for arranging bonding to a cell receptor and/or an active centre for transmitting an active function.

The term “derivative” means a peptide which may be derived from the above-mentioned peptides and/or fragments by homologous substitution, deletion or insertion of one or more amino acid(s) into or from the peptide chains.

The fumaric acid amides of the invention may be prepared in accordance with the above-mentioned U.S. patents to Blank.

In a third aspect, the present invention relates to drugs comprising a fumaric acid amide as defined above or mixtures thereof. The drugs obtained through the use according to the invention and/or through the use of the claimed fumaric acid amides may be present in forms suitable for oral, nasal, parenteral, rectal, pulmonal, ophthal or transdermal administration.

Preferably, the drug is intended for oral administration and is present in the form of tablets, coated tablets, capsules, granulate, solutions for drinking, liposomes, nano-capsules, micro-capsules, micro-tablets, pellets or powders as well as granulate, micro-tablets, pellets and powder filled in capsules, micro-tablets filled in capsules and powder filled in capsules.

According to a particularly preferred embodiment, the drug is a solid oral dosage form and, even more preferably, has an enteric coating (coating resistant to gastric acid). For example such a coating may be provided on tablets, coated tablets, micro-tablets, pellets or capsules.

As a matter of principle, the drug of the invention may contain suitable pharmaceutically acceptable carriers, excipients, additives etc. These are known to the person skilled in the art and do not require an explanation.

The use of micro-tablets or pellets is most preferred. Preferably, these have a mean diameter of 300 to 5000 μm, more preferably 300 to 2000 μm, when uncoated.

When administered parenterally by injection, the composition is present in a form suitable for this purpose. All customary liquid carriers suitable for injection may be used.

In any case, it is preferred that a single dose of the drug contains an amount of the fumaric acid amide of the formula (I) which corresponds or is equivalent to an amount of 1 to 500 mg, preferably 10 to 300 mg and most preferably 10 to 200 mg of fumaric acid. 

1. A fumaric acid amides of the general formula

wherein R¹ represents —OR³ or a D- or L-amino acid radical —NH—CHR⁴—COOH bonded via an amide bond, wherein R³ is hydrogen, a straight-chained, cyclic or branched, optionally substituted C₁₋₂₄ alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R⁴ is a side chain of a natural or synthetic amino acid, and R² represents a cyclosporine radical the ring of which may be cleaved at any peptide bond so as to enter into the fumaric acid amide bonding.
 2. A fumaric acid amide according to claim 1 wherein R¹ is said amino acid radical, —N—CHR⁴—COOH, wherein R⁴ is selected from the group of (i) side chains of polar amino acids (ii) side chains of charge amino acids.
 3. A fumaric acid amide according to claim 1 wherein R¹ is an L-amino acid radical, —N—CHR⁴—COOH, wherein R⁴ is selected from the group of (i) side chains of polar amino acids (ii) side chains of charge amino acids.
 4. A fumaric acid amide according to claim 1 wherein R³ is a straight-chained, cyclic or branched C₁₋₆ alkyl radical, a phenyl radical or a C₆₋₁₀ aralkyl radical.
 5. A fumaric acid amide according to claim 1 wherein R⁴ is a side chain of asparagine, glutamine, lysine, arginine, or histidine.
 6. A fumaric acid amide according to claim 1, wherein R¹ represents —OR³.
 7. A fumaric acid amide according to claim 1 wherein R¹ is NH—CHR⁴—COOH wherein R⁴ is selected from the group consisting of side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.
 8. A fumaric acid amide according to claim 1 wherein R³ is methyl or ethyl.
 9. A fumaric acid amide according to claim 1 wherein R¹ is —OR³ in which R³ is methyl or ethyl.
 10. A fumaric acid amide according to claim 1 wherein R¹ is —OR³ in which R³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2- or 3- hydroxypropyl, 2-methoxyethyl, 2,3-dihydroxypropyl, methoxymethyl or 2- or 3-methoxypropyl.
 11. A fumaric acid amide according to claim 1 wherein R¹ is —OR³ wherein R³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2- or 3- hydroxypropyl, 2-methoxyethyl, 2,3-dihydroxypropyl, methoxymethyl or 2- or 3-methoxypropyl.
 12. A fumaric acid amide according to any of claims 1–11 wherein the cyclosporine radical R² is cyclosporine A linearised before position 1 thereof.
 13. A pharmaceutical product comprising a fumaric acid amide of the formula

wherein R¹ represents —OR³ or a D- or L-amino acid radical —NH—CHR⁴—COOH bonded via an amide bond, wherein R³ is hydrogen, a straight-chained, cyclic or branched, optionally substituted C₁₋₂₄ alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R⁴ is a side chain of a natural or synthetic amino acid, and R² represents a cyclosporine radical the ring of which may be cleaved at any peptide bond so as to enter into the fumaric acid amide bonding.
 14. A pharmaceutical product according to claim 13 wherein the product is in a form suitable for oral, nasal, parenteral, rectal, pulmonal, ophthal or transdermal administration.
 15. A pharmaceutical product according to claim 13, said product being adapted for oral administration and being (i) in the form of tablets, coated tablets, capsules, granulate, solutions for drinking, liposomes, nano-capsules, micro-capsules, micro-tablets, pellets or powders; or (ii) in the form of granulate, micro-tablets, pellets or powder filled in capsules.
 16. A pharmaceutical product according to claim 15, said product being a solid oral dosage form and having an enteric coating.
 17. A pharmaceutical product according to claim 15 wherein said product is in the form of micro-tablets or pellets which without coating have a mean diameter of 300 to 5000 μm.
 18. A pharmaceutical product according to claim 15, wherein said product is in the form of micro-tablets or pellets which without coating have a mean diameter of 300 to 2000 μm.
 19. A pharmaceutical product according to claim 13, said product containing an amount of the fumaric acid amide of formula (II) per single dose which corresponds to 1 to 500 mg of fumaric acid.
 20. A pharmaceutical product according to claim 13, where R⁴ is selected from the group consisting of (i) side chains of polar amino acids and (ii) side chains of charged amino acids.
 21. A pharmaceutical product according to claim 13, said product containing an amount of the fumaric acid amide of formula (II) per single dose which corresponds to 10 to 300mg of fumaric acid.
 22. A pharmaceutical product according to claim 13 wherein R⁴ is a side chain of Asn, Glu, Lys, Arg, or His.
 23. A pharmaceutical product according to claim 13, wherein R¹ is —OR³.
 24. A pharmaceutical product according to any of claims 13–23 wherein the cyclosporine radical R² is cyclosporine A linearised before position 1 thereof.
 25. A method for preparing a pharmaceutical product, which method comprises formulating into a pharmaceutically-acceptable form for administration to a patient, at least one fumaric acid amide of the general formula:

wherein R¹ represents —OR³ or a D- or L-amino acid radical —NH—CHR⁴—COOH bonded via an amide bond, wherein R³ is hydrogen, a straight-chained, cyclic, or branched, optionally substituted C₁₋₂₄ alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R⁴ is a side chain of a natural or synthetic amino acid, and R² represents a cyclosporine radical the ring of which may be cleaved at any peptide bond so as to enter into the fumaric acid amide bonding.
 26. The method according to claim 25 where the pharmaceutical product is in a form suitable for oral, nasal, parenteral, rectal, pulmonal, ophthal or transdermal administration.
 27. The method according to claim 25 where the pharmaceutical product is in a solid form suitable for oral administration and has an enteric coating.
 28. The method according to claim 25 wherein the pharmaceutical product is in the form of micro-tablets or pellets, said micro-tablets or pellets without coating having a mean diameter of 300 to 5000 μm.
 29. The method according to claim 25 where the pharmaceutical product contains an amount of the fumaric acid amide of formula (I) per single dose which corresponds to 1 to 500 mg of fumaric acid.
 30. The method according to any of claims 25–29 wherein the cyclosporine radical R² is cyclosporine A linearised before position 1 thereof. 